The immune system is comprised of many different cell types, factors and organs. These include lymphocytes, monocytes and polymorphonuclear leukocytes, numerous soluble chemical mediators (cytokines and growth factors), the thymus, postnatal bone marrow, lymph nodes, liver and spleen. All of these components work together through a complex communication system to fight against microbial invaders such as bacteria, viruses, fungi and parasites, and against newly arising malignant (tumor) cells. NK cells are bone marrow-derived lymphocytes of the innate arm of the immune system. They are phenotypically defined as expressing the low affinity receptor for the Fc protein of IgG (FcRγIIIA, CD16) and CD 56 in the absence of T cell receptor and its associated CD3 complex (Perussia et al., 2005, Molecular Immunology 42: 385-395).
NK cells have vital importance as a first line of defense against infection and tumor proliferation while the adaptive immune system is being activated (French et al., 2003, Current Opinion in Immunology 15: 45-51). The primary role of NK cells is to eliminate infected or cancerous cells by direct cellular cytotoxicity (Van der Broek et al., 2000, Eur. J. Immunology 25: 3514-3516). The recognition mechanism involved does not utilize the major histocompatability class (MHC) I antigen presentation pathway and thus NK cells are neither antigen or MHC restricted and more importantly do not undergo clonal expansion to be effective (Trinchieri, 1989, Adv. Immunology 47: 176-187). In addition to their cytotoxic actions, NK cells have the ability to modulate the immune system by the production of plietropic cytokines upon cellular activation.
The activation of NK cells largely depends on NK triggering receptors, NKG2D, CD16 and the recently identified natural cytoxicity receptors (NCR) (Arnon et al., 2006, Seminars in Cancer Biology 16: 348-358), which include three members: NKp46, NKp44 and NKp30 (Moretta et al., 2002, Scand. J. Immunol. 55: 229-232, Bottino et al., 2005, Trends in Immunology 26: 221-226). The NCR have recently been designated cluster of differentiation notation, with NKp44 designated CD336.
CD336 encodes a 44 kDa surface glycoprotein characterized by a protein backbone of approximately 29 kDa (Vitale et al., 1998, J. Exp. Med. 187: 2065-2072). CD336 is not expressed on resting but only on activated NK cells, thus the surface display of CD336 can be used as a surrogate marker of NK activation (Moretta et al., 2001, Annu. Rev. Immunol. 19: 197-223). While CD336 is a pertinent marker of cell activation, the hallmark of NK functionality is the ability to lyse target cells, typically NK lytic activity is measured in vitro using a cell line deficient for surface MHC I expression such as the K562 tumor cell line.
The present inventors have identified novel methods for inducing an NK cell-mediated immune response, for increasing the activity of NK cells and for assessing and detecting an NK cell response in connection with the treatment of viruses and tumors.